ZUMA-23: A global, phase 3, randomized controlled study of axicabtagene ciloleucel versus standard of care as first-line therapy in patients with high-risk large B-cell lymphoma.
Authors: Jason Westin, Caron Alyce Jacobson, Julio C. Chavez, Anna Sureda, Franck Morschhauser, Bertram Glaß, Michael Dickinson, Andrew Davies, Ian W. Flinn, David G. Maloney, Martine Chamuleau, Michael Timothy Tees, Allen Xue, Shilpa Shahani, Olga Nikolajeva, Janet Kang, Aida Kaplan, Marco Andreas Schupp, Harry Miao, Elizabeth Shima Rich
Journal: Journal of Clinical Oncology (2023)

TPS7578 Background: The nearly 40% of patients (pts) with large B-cell lymphoma (LBCL) who are refractory to or relapse after current first-line (1L) standard-of-care (SOC) regimens, such as R-CHOP (rituximab [R] + cyclophosphamide [C], doxorubicin [H], vincristine [O], and prednisone [P]) and DA-EPOCH-R (dose-adjusted etoposide [DA-E]), have poor prognoses. High International Prognostic Index (IPI) score and the subtype of high-grade B-cell lymphoma (HGBL) are associated with shorter progression-free and overall survival (PFS and OS; Nastoupil LJ and Bartlett NL. J Clin Oncol. 2023). Strategies to improve outcomes in these subgroups have been largely unsuccessful; therefore, therapeutic options with a different mechanism of action are needed. Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved to treat pts with relapsed/refractory (R/R) LBCL after demonstrating significant clinical benefit as 2L (ZUMA-7; Locke FL, et al. N Engl J Med. 2022) and ≥3L (ZUMA-1; Neelapu SS, et al. N Engl J Med. 2017) therapy. Additionally, in the Phase 2 ZUMA-12 study in pts with refractory 1L LBCL, axi-cel showed a high rate of durable responses with an objective response rate of 89% (complete response rate, 78%) and an ongoing response rate of 73% (median follow-up, 15.9 mo; Neelapu SS, et al. Nat Med. 2022). ZUMA-23 is the first Phase 3, randomized controlled study to evaluate CAR T-cell therapy as a 1L regimen for any cancer and will assess axi-cel versus SOC in pts with high-risk LBCL, defined as IPI 4-5. Methods: The Phase 3 trial design will enroll ≈300 adult pts with high-risk, histologically confirmed LBCL based on the 2016 WHO classification, including diffuse large B-cell lymphoma (DLBCL), HGBL, and transformed follicular or marginal zone lymphoma (Swerdlow SH, et al. Blood. 2016). Eligible pts will receive 1 cycle of R-chemotherapy and then be randomized 1:1 to receive axi-cel or continue with SOC. Pts in the axi-cel arm will undergo leukapheresis and then receive R-CHOP or DA-EPOCH-R as bridging therapy, followed by lymphodepleting chemotherapy (fludarabine/cyclophosphamide), and a single axi-cel infusion (2×10 6 CAR T cells/kg). Prophylactic corticosteroids may be administered to reduce the incidence and severity of cytokine release syndrome at the investigator’s discretion. Pts in the SOC arm will receive 5 additional cycles of R-CHOP or DA-EPOCH-R (investigator’s choice). The primary endpoint is event-free survival by blinded central review. Key secondary endpoints are OS and PFS. Safety, quality of life, and pharmacokinetics will also be assessed. Pts with a history of HIV and/or hepatitis B or C and undetectable viral loads may enroll. Key exclusion criteria include LBCL of the central nervous system. ZUMA-23 is open for enrollment (NCT05605899). Clinical trial information: NCT05371093 .